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A interacção gene-gene afecta o risco de doença coronária
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Advisor(s)
Abstract(s)
Introdução: Existem vários estudos que
comparam doentes coronários e controlos, no
sentido de determinar quais os polimorfismos
que apresentam risco acrescido de doença das
artérias coronárias (DC). Os seus resultados
têm sido muitas vezes contraditórios, mas
apresentam uma limitação suplementar:
avaliam os polimorfismos um a um, quando
na natureza os polimorfismos não existem
isolados. Põe-se a questão se serão mais
importantes associações de polimorfismos
mutados no mesmo gene ou em genes
diferentes.
Objectivo: Com o presente trabalho
pretendemos avaliar o risco da associação de
polimorfismos em termos de aparecimento de
DC no mesmo gene ou em genes diferentes.
Metodologia: Estudámos em 298 doentes
coronários e 298 controlos sãos o risco
associado aos polimorfismos (genótipos
considerados de risco), DD da Enzima de
Converaão da Angiotensina (ECA) I/D; GG da
ECA 8, MM do Angiotensinogénio (AGT) 174;
TT do AGT 235; TT da Metiltetrahidrofolato
Reductase (MTHFR) 677; AA da MTHFR
1298;RR da Paraoxonase1 (PON1) 192 e MM
da PON1 55. Posteriormente avaliámos o risco
ligado às associações no mesmo gene (DD da
ECA + GG da ECA 8; MM do AGT174 + TT
do AGT 235; TT da MTHFR 677 + AA da
MTHFR 1298). Finalmente, nos polimorfismos
que isoladamente apresentavam significância,
avaliámos o risco das associações de
polimorfismos a níveis funcionais diferentes (ECA + AGT; ECA + MTHFR; ECA + PON1.
Finalmente através de um modelo de regressão
logística fomos determinar quais as variáveis
que se relacionavam de forma significativa e
independente com a DC.
Resultados: Os polimorfismos isolados como:
ECA DD [P<0.0001], ECA 8 GG [P=0,023],
e MTHFR 1298 AA [P=0,049]), apresentaram
uma frequência mais elevada nos casos,
associando-se de forma significativa ao grupo
com DC. A associação de polimorfismos no
mesmo gene não teve efeito sinergístico ou
aditivo e não aumentou o risco de DC. A
associação polimórfica em genes diferentes
aumentou o risco de DC quando comparada
com o risco do polimorfismo isolado. No caso
da associação da ECA DD ou ECA 8 GG
com a PON1 192 RR, o risco quadruplicou
(OR passou de 1,8 para 4,2). Após regressão
logística o hábito tabágico, a história familiar,
o fibrinogénio, diabetes, a associação ECA
DD ou ECA 8 GG com a MTHFR 1298 AA
e a interacção ECA DD ou ECA 8 GG com
a PON1 192 RR permaneceram na equação,
mostrando ser factores de risco independente
para DC.
Conclusões: A associação de polimorfismos
mutados no mesmo gene nunca aumentou o
risco do polimorfismo isolado. A associação
com interacção de polimorfismos mutados
em genes diferentes, pertencentes a sistemas
fisiopatológicos e enzimáticos diferentes,
esteve sempre associada a maior risco do
que cada polimorfismo por si. Este trabalho
levanta, pela primeira vez, a possibilidade
de tentativa de compreensão do risco
genético coronário em conjunto e não de cada
polimorfismo por si.
Introduction: Various studies have compared coronary artery disease (CAD) patients with controls in order to determine which polymorphisms are associated with a higher risk of disease. The results have often been contradictory. Moreover, these studies evaluated polymorphisms in isolation and not in association, which is the way they occur in nature. Objective: Our purpose was to evaluate the risk of CAD in patients with associated polymorphisms in the same gene or in different genes. Methods: We evaluated the risk associated with ACE DD, ACE 8 GG, AGT 174MM, AGT 235TT, MTHFR 677TT, MTHFR 1298AA, PON1 192RR and PON1 55MM in 298 CAD patients and 298 healthy individuals. We then evaluated the risk of associated polymorphisms in the same gene (ACE DD + ACE 8 GG; AGT 174MM + AGT 235TT; MTHFR 677TT + MTHFR 1298AA). Finally, for the isolated polymorphisms which were significant, we evaluated the risk of polymorphism associations at different functional levels (ACE + AGT; ACE + MTHFR; ACE + PON1). Multiple logistic regression was used to identify independent risk factors for CAD. Results: Isolated polymorphisms including ACE DD (p<0.0001), ACE 8 GG (p=0.023), and MTHFR 1298AA (p=0.049) presented with a significantly higher frequency in the CAD group. An association of polymorphisms in the same gene did not have an additive or synergistic effect, nor did it increase the risk of CAD. Polymorphic associations in different genes increased the risk of CAD, compared with the isolated polymorphisms. The association of ACE DD or ACE 8 GG with PON1 192RR increased the risk of CAD fourfold (1.8 to 4.2). After logistic regression analysis, current smoking, family history, fibrinogen, diabetes, and the ACE DD or ACE 8 GG + MTHFR 1298AA and ACE DD or ACE 8 GG + PON1 192RR associations remained in the model and proved to be independent predictors of CAD. Conclusions: The association of polymorphisms in the same gene did not increase the risk of the isolated polymorphism. The association of polymorphisms in genes belonging to different enzyme systems was always linked to increased risk compared to the isolated polymorphisms. This study may contribute to a better understanding of overall genetic risk for CAD rather than that associated with each polymorphism in isolation.
Introduction: Various studies have compared coronary artery disease (CAD) patients with controls in order to determine which polymorphisms are associated with a higher risk of disease. The results have often been contradictory. Moreover, these studies evaluated polymorphisms in isolation and not in association, which is the way they occur in nature. Objective: Our purpose was to evaluate the risk of CAD in patients with associated polymorphisms in the same gene or in different genes. Methods: We evaluated the risk associated with ACE DD, ACE 8 GG, AGT 174MM, AGT 235TT, MTHFR 677TT, MTHFR 1298AA, PON1 192RR and PON1 55MM in 298 CAD patients and 298 healthy individuals. We then evaluated the risk of associated polymorphisms in the same gene (ACE DD + ACE 8 GG; AGT 174MM + AGT 235TT; MTHFR 677TT + MTHFR 1298AA). Finally, for the isolated polymorphisms which were significant, we evaluated the risk of polymorphism associations at different functional levels (ACE + AGT; ACE + MTHFR; ACE + PON1). Multiple logistic regression was used to identify independent risk factors for CAD. Results: Isolated polymorphisms including ACE DD (p<0.0001), ACE 8 GG (p=0.023), and MTHFR 1298AA (p=0.049) presented with a significantly higher frequency in the CAD group. An association of polymorphisms in the same gene did not have an additive or synergistic effect, nor did it increase the risk of CAD. Polymorphic associations in different genes increased the risk of CAD, compared with the isolated polymorphisms. The association of ACE DD or ACE 8 GG with PON1 192RR increased the risk of CAD fourfold (1.8 to 4.2). After logistic regression analysis, current smoking, family history, fibrinogen, diabetes, and the ACE DD or ACE 8 GG + MTHFR 1298AA and ACE DD or ACE 8 GG + PON1 192RR associations remained in the model and proved to be independent predictors of CAD. Conclusions: The association of polymorphisms in the same gene did not increase the risk of the isolated polymorphism. The association of polymorphisms in genes belonging to different enzyme systems was always linked to increased risk compared to the isolated polymorphisms. This study may contribute to a better understanding of overall genetic risk for CAD rather than that associated with each polymorphism in isolation.
Description
Keywords
Enzima conversora da angiotensina Polimorfismo genético Factores de risco Interacção gene-gene Doença coronária Angiotensin-converting enzyme Genetic polymorphism Risk factors Gene-gene interaction Coronary artery disease . Faculdade de Ciências da Vida
Citation
Mendonça, M. I., dos Reis, R. P., Freitas, A. I., Sousa, A. C., Pereira, A., Faria, P., ... & Cardoso, A. A. (2009). A interacção gene-gene afecta o risco de doença coronária. Revista Portuguesa de Cardiologia, 28(4), 397-415.